Process for synthesizing d-tocotrienols from 2-vinylchromane compound

Abstract

A process of forming a d-tocotrienol from a (2S)-vinylchromane compound, through hydroboration of the (2S)-vinylchromane to provide an organoborane, followed by coupling the organoborane with a halogenated C-14 sidechain compound under conditions of palladium-catalyzed cross-coupling is taught. Methods for providing the (2S)-vinylchromane compound and the halogenated C-14 compound are disclosed.

1. A process of forming a d-tocotrienol comprising:
 a) providing a (2S)-vinylchroman compound having the formula shown by (I), in single enantiomer form;                  
 
 b) converting said (2S)-vinylchroman compound of (I) to an organoborane having the formula shown by (II) by way of a hydroboration reaction; and                  
 
 c) providing 1-bromo-2,6,10-trimethylundeca-1E,5E,9-triene or 1-iodo-2,6,10-trimethylundeca-1E,5E,9-triene; 
 d) coupling said organoborane of (H) with 1-bromo-2,6,10-trimethylundeca-1E,5E,9-triene or 1-iodo-2,6,10-trimethylundeca-1E,5E,9-triene, under conditions of palladium-catalyzed cross-coupling to form a d-tocotrienol product of formula (III),                  
 
 
       wherein R 1  is a hydrogen atom or methyl group, R 2  is a hydrogen atom or methyl group, and R 3  is a methyl group, except that R 1  and R 2  are not both methyl groups, further wherein P is a hydrogen atom or a protecting group. 
     
     
       2. The process according to  claim 1  wherein P is hydrogen or a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, benzyl ether, tetrahydropyranyl ether, and a trialkylsilyl ether R 3 Si wherein the alkyl groups are chosen from the set of C 1 –C 6  straight chain or branched chain alkyl groups. 
     
     
       3. The process according to  claim 1  wherein said P is hydrogen and said organoborane is coupled with 1-iodo-2,6,10-trimethylundeca-1E,5E,9-triene. 
     
     
       4. The process according to  claim 1  wherein said d-tocotrienol product produced is in greater than 90.0 percent of the (R) enantiomeric form. 
     
     
       5. The process according to  claim 1  wherein said d-tocotrienol product formed is d-beta-tocotrienol, wherein each of R 1  and R 3  is a methyl group and R 2  is a hydrogen atom. 
     
     
       6. The process according to  claim 1  wherein said d-tocotrienol product formed is d-gamma-tocotrienol, wherein R 1  is a hydrogen atom and each of R 2  and R 3  is a methyl group. 
     
     
       7. The process according to  claim 1  wherein said d-tocotrienol product formed is d-delta-tocotrienol, wherein each of R 1  and R 2  is a hydrogen atom and R 3  is a methyl group. 
     
     
       8. The process according to  claim 1  wherein said hydroboration reaction is conducted using a dialkylborane reagent selected from the group consisting of dicyclohexylborane, diisopropylborane, disiamylborane, and 9-borabicyclo[3.3.1]nonane. 
     
     
       9. The process according to  claim 1  wherein said step of providing said (2S)-vinylchroman compound of (I), in single enantiomer form is conducted by a method comprising the steps of
 a) providing a 2-chroman aldehyde compound having the formula shown by (IV), in single enantiomer form; and                  
 
 b) converting said 2-chroman aldehyde to said (2S)-vinylchroman compound of (I) by way of a Wittig olefination reaction, 
 
       wherein R 1  is a hydrogen atom or methyl group, R 2  is a hydrogen atom or methyl group, and R 3  is a methyl group, and 
       further wherein P is hydrogen or a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, benzyl ether, tetrahydropyranyl ether, and a trialkylsilyl ether R 3 Si wherein the alkyl groups are chosen from the set of C 1 –C 6  straight chain or branched chain alkyl groups. 
     
     
       10. The process according to  claim 9  wherein said step of providing a 2-chroman aldehyde compound having the formula shown by (IV) is conducted by a method comprising the steps of
 a) providing a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the formula shown by (V), in single enantiomer form; and                  
 
 b) oxidizing said (2S)-chroman alcohol of (V) to provide the single enantiomer (2S)-chroman aldehyde of formula (IV), 
 
       wherein R 1  is a hydrogen atom or methyl group, R 2  is a hydrogen atom or methyl group, and R 3  is a methyl group. 
     
     
       11. The process according to  claim 10  wherein said step of providing a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the structure shown by (V), in single enantiomer form is conducted by a method comprising the steps of
 a) providing methyl-2-methyl-4-hydroxy-2-butenoate; 
 b) reacting said methyl-2-methyl-4-hydroxy-2-butenoate with 2,5-dimethylhydroquinone under the influence of Lewis acid catalysis to provide the substituted hydroquinone having the structure of formula (VI);                  
 
 c) cyclizing said substituted hydroquinone of (VI) under the influence of a protic or Bronsted acid to provide a racemic chroman ester having the structure of formula (VII);                  
 
 d) reducing said racemic chroman ester of (VII) to its corresponding racemic chroman alcohol; and 
 e) resolving said racemic chroman alcohol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound, 
 
       wherein R 1  is a hydrogen atom or methyl group, R 2  is a hydrogen atom or methyl group, and R 3  is a methyl group, and 
       further wherein P is hydrogen or a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, benzyl ether, tetrahydropyranyl ether, and a trialkylsilyl ether R 3 Si wherein the alkyl groups are chosen from the set of C 1 –C 6  straight chain or branched chain alkyl groups. 
     
     
       12. The process according to  claim 10  wherein said step of providing a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound having the structure shown by (V), in single enantiomer form is conducted by a method comprising the steps of
 a) reacting a protected 2,5-dimethylhydroquinone with 3-methyl-3-hydroxy-1,4-pentadiene under the influence of a Bronsted acid to form a racemic 2-vinyl-2,5,8-trimethylchroman-6-ol having the structure of formula (VIII);                  
 
 b) oxidatively cleaving said vinylchroman compound of (VIII) to form a chroman-2-aldehyde having the structure of formula (IX);                  
 
 c) reducing said chroman-2-aldehyde of (IX) to its corresponding racemic chroman-2-alcohol; and 
 (d) resolving said racemic chroman-2-alcohol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (V), 
 
       wherein R 1  is a hydrogen atom or methyl group, R 2  is a hydrogen atom or methyl group, and R 3  is a methyl group, and 
       further wherein P is hydrogen or a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, benzyl ether, tetrahydropyranyl ether, and a trialkylsilyl ether R 3 Si wherein the alkyl groups are chosen from the set of C 1 –C 6  straight chain or branched chain alkyl groups. 
     
     
       13. The process according to  claim 10  wherein said step of providing a (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (V), in single enantiomer form is conducted by a method comprising the steps of
 a) reacting a protected 2,5-dimethyl-3-bromohydroquinone molecule with isoprene oxide (1-methyl-1-vinyloxirane) under the influence of a palladium catalyst to provide an allylic ether compound having the structure of formula (X);                  
 
 b) adding a protecting group to the primary hydroxyl group of said allylic ether compound of formula (X) to form a protected allylic ether compound having the structure of (XI);                  
 
 c) cyclizing said protected allylic ether compound of (XI) using a Heck reaction to form a 3-chromene derivative having the structure of (XII);                  
 
 d) hydrogenating said 3-chromene derivative of (XII) by way of catalytic hydrogenation to form a diprotected racemic 2,5,8-trimethylchroman-2-methanol; 
 e) removing the protecting groups from said diprotected racemic 2,5,8-trimethylchroman-2-methanol to provide a racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol; and 
 f) resolving said racemic 2,5,8-trimethyl-6-hydroxychroman-2-methanol to form said (2S) 2-hydroxymethyl-6-hydroxy-alklychroman compound of formula (V), wherein R 1  is a hydrogen atom or methyl group, R 2  is a hydrogen atom or methyl group, and R 3  is a methyl group, and 
 
       further wherein P is hydrogen or a protecting group selected from the group consisting of p-toluenesulfonate ester, benzenesulfonate ester, methanesulfonate ester, benzyl ether, methyl ether, 2-tetrahydropyranyl ether, and 2-tetrahydrofuranyl ether, benzyl ether, tetrahydropyranyl ether, and a trialkylsilyl ether R 3 Si wherein the alkyl groups are chosen from the set of C 1 –C 6  straight chain or branched chain alkyl groups. 
     
     
       14. The process according to  claim 1  wherein said step of providing 1-iodo-2,6,10-trimethylundeca-1E,5E,9-triene is conducted by treating 3,7,11-trimethyldodeca-2E,6E,10-trienoic acid with a lead tetraacetate and iodine. 
     
     
       15. The process according to  claim 1  wherein said step of providing 1-bromo-2,6,10-trimethylundeca-1E,5E,9-triene is conducted by treating 3,7,11-trimethyldodeca-2E,6E,10-trienoic acid with a lead tetraacetate and bromine.